A. Proliferative Disorders
Extracellular signals received at transmembrane receptors are relayed into the cells by signal transduction pathways (Pelech et al., Science 257:1335 (1992)) which have been implicated in induction of cell proliferation, differentiation or apoptosis (Davis et al., J. Biol. Chem. 268:14553 (1993)). One such signal transduction pathway is the mitogen activated protein kinase (MAPK) cascade. See, Nishida et al., Trends Biochem. Sci. 18:128 (1993) and Blumer et al., Trends Biochem. Sci. 19:236 (1994). Much of the MAPK pathway is conserved over different species. The most thoroughly studied of the MAPKs are extra cellular signal regulated kinases (ERKs) (Posada et al., Science 255:212 (1992); Biggs III et al., PNAS. USA 89:6295 (1992); and Garner et al., Genes Dev. 6:1280 (1992)) and c-Jun NH2 terminal kinases (JNKs) (Hibi et al., Genes Dev. 7:2135 (1993)). JNKs are members of a class of stress activated protein kinases (SAPK) and are shown to be activated by treatment of cells with UV radiation, pro-inflammatory cytokines and environmental stress (Derijard et al., Cell 1025 (1994)). Activation of ERK has been shown to involve kinase mediated phosphorylation of threonine and tyrosine residues, which signals cell proliferation. In contrast, activation of JNKs leads to cell growth inhibition and apoptosis.
Protein tyrosine kinases are enzymes which catalyze a well defined chemical reaction: the phosphorylation of a tyrosine residue (Hunter et al., Ann. Rev. Biochem. 54:897 (1985)). Receptor tyrosine kinases in particular are attractive targets for drug design since blockers for the substrate domain of these kinases is likely to yield an effective and selective antiproliferative agent. The potential use of protein tyrosine kinase blockers as antiproliferative agents was recognized as early as 1981, when quercetin was suggested as a PTK blocker (Graziani et al., Eur. J. Biochem. 135:583-589 (1983)).
The best understood MAPK pathway involves extracellular signal-regulated kinases which constitute the Ras/Raf/MEK/ERK kinase cascade (Boudewijn et al., Trends Biochem. Sci. 20, 18 (1995)). Once this pathway is activated by different stimuli, MAPK phosphorylates a variety of proteins including several transcription factors which translocate into the nucleus and activate gene transcription. Negative regulation of this pathway could arrest the cascade of these events.
B. Angiogenesis Inhibition
Angiogenesis, or development of new blood vessels, is implicated in a host of diseases including tumorigenesis, metastasis and tumor growth, retinopathies, neovascular ocular disorders, and postangioplasty or postatherectomy restenosis. See, Bicknell et al. (1996) Curr. Opin. Oncol. 8: 60-65; Gariano et al. (1996) Survey Ophthalmol. 40: 481-490; and Wilcox, J. N. (1993) Am. J. Cardiol. 72: 88E-95E).
Recent research has indicated that differences in the production of vascular endothelial growth factor (VEGF) and sFlt-1 by smooth muscle cells and human umbilical endothelial cells (HUVECs) are consistent with the role of these cells in angiogenesis. See, Belgore et al., Eur. J. Clin. Invest. 2003, 33(10), page 833-39. Studies have indicated a therapeutic potential of placental growth factor (PlGF) and its receptor FLT1 in angiogenesis. An antibody against FLT1 has been shown to suppress neovascularization in tumors and ischemic retina, and angiogenesis and inflammatory joint destruction in autoimmune arthritis. See, Luttun et al., Nat Med., 2002, 8(8) page 831-40.
Expression and secretion of angiogenic factors by tumors has been investigated. It has been suggested that because tumors express multiple angiogenic factors, broad spectrum antagonists of angiogenesis can provide effective means of tumor stabilization. Anti-angiogenic approaches to tumor therapy have been defined to involve interference with growth, migration and differentiation of blood vessels associated with tumor growth. Anti-angiogenic agents have been categorized to include protease inhibitors, modulators of cytokines, heparin-like molecules, and antagonists of vascular growth factors. Growth factor antagonists have been categorized to include heparin-like molecules, angiogenin antagonists, antisense fibroblast growth factor, DS 4152, suramin analogs, and protein-bound saccharide-K (Bicknell et al., Id.).
C. Biological Activity of Curcumin
Curcumin is a compound that is isolated from the commonly used spice turmeric. The structure of curcumin is shown in Scheme 1.

Curcumin has been shown to inhibit the progression of chemically induced colon and skin cancers in animal models. In HT29 cells curcumin-induced modulation of genes involved in transition through the G2/M phase has been observed to correspond to a cell cycle arrest in the G2/M phase. See, van Erk et al., J. of Carcinogenesis 2004, 3:8. Curcumin has also been observed to downregulate expression of some cytochrome P450 genes and to affect expression of metallothionein genes, tubulin genes, p53 and other genes involved in colon carcinogenesis. Id.
The antiproliferative effects of curcumin are believed to be related to inhibition of aminopeptidase N (APN), an enzyme that is linked to invasiveness and angiogenesis in tumors. See, Kwon et al., Chem. Biol., 10, 695 (2003). Curcumin has also been shown to have direct antiangiogenic activity in vitro and in vivo. See, Arbiser et al., Mol Med., 1998, 4(6): page 376-83.
Curcumin has also been shown to be effective in the dinitrobenzene sulfuric acid (DNB) induced murine colitis model, which is an experimental model of IBD. See, Salh et al., Am. J Phys. Gastrointestinal and Liver Physiology, 2003 285(1), page 235-43. In the DNB-induced murine colitis model, curcumin was observed to attenuate macroscopic damage, to improve intestinal cell function, and to inhibit the nuclear transcription factor NF-κB activation in the colon.
Curcumin is also effective in biological assays that are predictive of activity in age-related neurodegenerative diseases such as Alzheimer's Disease (AD) and presenile dementia. Curcumin has been shown to reduce the oxidative damage (isoprostane levels) and synaptophysin loss induced by intracerebroventricular infusion of beta amyloid (Abeta) peptides. See, Chu et al., Neurobiol. Aging, 2001, 22(6): page 993-1005.
Cancer and other proliferative disorders remain a major unmet medical need. Cancer treatments often comprise surgery, chemotherapeutic treatments, radiation treatment or combinations thereof. Chemotherapeutic treatments for most cancers only delay disease progression rather than providing a cure. Cancers often become refractory to chemotherapy via development of multidrug resistance. Particular cancers are inherently resistant to some classes of chemotherapeutic agents. See DeVita et al, Principles of Cancer Management: Chemotherapy. In: Cancer. Principles and Practice of Oncology, 5th edition, Lippincott-Raven, Philadelphia, N.Y. (1977), pp. 333-347.
Progress continues in treatment of proliferative disorders such as cancer, and in the treatment of angiogenesis-mediated disorders. However, there remains a need to develop new therapeutic agents.